GDNF â a stranger in the TGFâβ superfamily?

Glial cell line‐derived neurotrophic factor (GDNF) family, consisting of GDNF, neurturin, artemin and persephin are distant members of the transforming growth factor‐I² (TGF‐I²) superfamily. Unlike other members of the TGF‐I² superfamily, which signal through the receptor serine‐threonine kinases, GDNF family ligands activate intracellular signalling cascades via the receptor tyrosine kinase Ret. GDNF family ligands first bind to the glycosylphosphatidylinositol (GPI)‐anchored GDNF family receptor I± (GFRI±) and then the GDNF family ligand–GFRI± complex binds to and stimulates autophosphorylation of Ret. Alternatively, a preassociated complex between GFRI± and Ret could form the binding site for the GDNF family ligand. GFRI±1, GFRI±2, GFRI±3 and GFRI±4 are the physiological coreceptors for GDNF, neurturin, artemin and persephin, respectively. Although all GDNF family ligands signal via activated Ret, GDNF can signal also via GFRI±1 in the absence of Ret. GPI‐anchored GFRI± receptors are localized in plasma membrane to lipid rafts. GDNF binding to GFRI±1 also recruits Ret to the lipid rafts and triggers association with Src, which is required for effective downstream signalling, leading to differentiation and neuronal survival. GDNF family ligands are potent survival factors for midbrain dopamine neurons, motoneurons, noradrenergic neurons, as well as for sympathetic, parasympathetic and sensory neurons. However, for most neuronal populations, except for motoneurons, TGF‐I² is required as a cofactor for GDNF family ligand signalling. Because GDNF and neurturin can rescue dopamine neurons in the animal models of Parkinson disease, as well as motoneurons in vivo, hopes have been raised that GDNF family ligands may be new drugs for the treatment of neurodegenerative diseases. GDNF also has distinct functions outside the nervous system, promoting ureteric branching in kidney development and regulating spermatogenesis.